CN102764248A - 替普瑞酮防治吗啡所致的肝脏损伤的用途 - Google Patents
替普瑞酮防治吗啡所致的肝脏损伤的用途 Download PDFInfo
- Publication number
- CN102764248A CN102764248A CN201210240755XA CN201210240755A CN102764248A CN 102764248 A CN102764248 A CN 102764248A CN 201210240755X A CN201210240755X A CN 201210240755XA CN 201210240755 A CN201210240755 A CN 201210240755A CN 102764248 A CN102764248 A CN 102764248A
- Authority
- CN
- China
- Prior art keywords
- morphine
- teprenone
- gga
- group
- liver
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 title claims abstract description 109
- 229960005181 morphine Drugs 0.000 title claims abstract description 53
- DJAHKBBSJCDSOZ-AJLBTXRUSA-N (5z,9e,13e)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one;(5e,9e,13e)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CC\C(C)=C/CCC(C)=O.CC(C)=CCC\C(C)=C\CC\C(C)=C\CC\C(C)=C\CCC(C)=O DJAHKBBSJCDSOZ-AJLBTXRUSA-N 0.000 title claims abstract description 30
- 229950006156 teprenone Drugs 0.000 title claims abstract description 30
- 206010067125 Liver injury Diseases 0.000 title abstract 3
- 231100000753 hepatic injury Toxicity 0.000 title abstract 3
- 230000002265 prevention Effects 0.000 title description 3
- 239000003814 drug Substances 0.000 claims abstract description 12
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 210000005229 liver cell Anatomy 0.000 abstract description 6
- 230000006907 apoptotic process Effects 0.000 abstract description 5
- 230000006378 damage Effects 0.000 abstract description 4
- 208000027418 Wounds and injury Diseases 0.000 abstract description 2
- 208000014674 injury Diseases 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 150000002632 lipids Chemical class 0.000 abstract 1
- 230000003617 peroxidasic effect Effects 0.000 abstract 1
- 230000003313 weakening effect Effects 0.000 abstract 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
- 210000004185 liver Anatomy 0.000 description 17
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 description 15
- 239000007924 injection Substances 0.000 description 14
- 238000002347 injection Methods 0.000 description 14
- 239000011780 sodium chloride Substances 0.000 description 14
- 241000699670 Mus sp. Species 0.000 description 11
- 108090000397 Caspase 3 Proteins 0.000 description 7
- 102100029855 Caspase-3 Human genes 0.000 description 7
- 102000004039 Caspase-9 Human genes 0.000 description 7
- 108090000566 Caspase-9 Proteins 0.000 description 7
- 230000004913 activation Effects 0.000 description 6
- 210000002784 stomach Anatomy 0.000 description 6
- 230000008520 organization Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 238000001262 western blot Methods 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 229920001213 Polysorbate 20 Polymers 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 238000011010 flushing procedure Methods 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 3
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 3
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- AVWQQPYHYQKEIZ-UHFFFAOYSA-K trisodium;2-dodecylbenzenesulfonate;3-dodecylbenzenesulfonate;4-dodecylbenzenesulfonate Chemical compound [Na+].[Na+].[Na+].CCCCCCCCCCCCC1=CC=C(S([O-])(=O)=O)C=C1.CCCCCCCCCCCCC1=CC=CC(S([O-])(=O)=O)=C1.CCCCCCCCCCCCC1=CC=CC=C1S([O-])(=O)=O AVWQQPYHYQKEIZ-UHFFFAOYSA-K 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 230000003859 lipid peroxidation Effects 0.000 description 2
- 229940124636 opioid drug Drugs 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 101100507655 Canis lupus familiaris HSPA1 gene Proteins 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 1
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 240000005373 Panax quinquefolius Species 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- 206010042434 Sudden death Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 208000012998 acute renal failure Diseases 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 230000001120 cytoprotective effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 210000000274 microglia Anatomy 0.000 description 1
- 230000006676 mitochondrial damage Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229960005195 morphine hydrochloride Drugs 0.000 description 1
- XELXKCKNPPSFNN-BJWPBXOKSA-N morphine hydrochloride trihydrate Chemical compound O.O.O.Cl.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O XELXKCKNPPSFNN-BJWPBXOKSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000751 protein extraction Methods 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及替普瑞酮在制备防治吗啡所致的肝脏损伤的药物中的新用途，本发明公开了替普瑞酮可以保护肝脏细胞免受吗啡的毒害，可以抑制吗啡引起的细胞凋亡，减弱吗啡所致的脂质过氧化损伤，替普瑞酮可用于吗啡所致的肝脏损伤的预防与治疗。
Description
技术领域
本发明涉及一种替普瑞酮的新用途，具体是替普瑞酮在制备预防吗啡所致的肝脏损伤的药物中的应用，属于医药技术领域。
背景技术
阿片类药物的滥用已经成为国内外关注的严重的社会问题。吗啡作为一种强有效的镇痛剂常用于治疗急性和慢性疼痛，是阿片类药物的一种。但长期应用吗啡会导致多个系统和器官的细胞死亡和凋亡，其临床应用受到很大的限制 （Nestler EJ, Aghajanian GK. Molecular and cellular basis of addiction. Science. 1997；278：58-63. Yin D, Mufson RA, Wang R, Shi Y. Fas-
Mediated cell death promoted by opioids. Nature. 1999; 397-218. Hu S, Sheng WS, Lokensgard JR, Peterson PK. Morphine induces apoptosis of human microglia and neurons. Neuropharmacology. 2002；42：829—836.）。其中，吗啡对肝脏的损害是显著而又严重的，这已是为医学界所证实的事实。寻找保护吗啡所致的肝脏损伤的药物对于降低吗啡的副作用及更广泛地应用吗啡具有重要的意义。
替普瑞酮（geranylgeranylacetone, GGA），即6，10，14，18-四甲基-5，9，13，17-十九烷四烯-2-酮的单顺式和全反式异构体的混合物，现已被广泛应用于消化道溃疡的治疗中。近年研究发现，GGA对光损伤、缺血性肾衰竭、癫痫和脑梗塞等疾病具有防治作用(Tanito M, Kwon Y.W, Kondo N, Bai J, Masutani H, Nakamura H, Fujii J, Ohira A, Yodoi J. Cytoprotective effects of geranylgeranylacetone against retinal photooxidative damage, J Neurosci 2005; 25, 2396-404; Suzuki S, Maruyama S, Sato W, Morita Y, Sato F, Miki Y, Kato S, Katsuno M, Sobue G, Yuzawa Y, Matsuo S. geranylgeranylacetone ameliorates ischemic acute renal failure via induction of Hsp70. Kidney Int 2005;67:2210-20; Fujiki M, Kobayashi H, Inoue R, Tatsuya R, Ishii K. Single oral dose of geranylgeranylacetone for protection against delayed neuronal death induced by transient ischemia. Brain Res 2004;1020:210-213; Yasuda H, Shichinohe H, Kuroda S, Ishikawa T, Iwasaki Y. Neuroprotective effect of a heat shock protein inducer, geranylgeranylacetone in permanent focal cerebral ischemia. Brain Res 2005;1032:176-182)。替普瑞酮是否可以用于防治吗啡所致的肝脏损伤尚未见报道。
发明内容
本发明的目的是提供一种替普瑞酮的新用途，即替普瑞酮在制备预防吗啡所致的肝脏损伤药物中的应用。
本发明所述的应用是以替普瑞酮为活性成分在制备预防和/或治疗吗啡所致的肝脏损伤的的作用。
本发明所述应用中还可以加入一种或多种药物上可接受的辅料，所述辅料包括药学领域常规的填充剂、稀释剂、粘合剂、赋形剂、吸收促进剂、填充剂、表面活性剂和稳定剂等，必要时还可加入香味剂、色素和甜味剂等。
本发明所述应用除制成胶囊外，还可以制成丸剂、粉剂、片剂、粒剂、口服液和注射液等多种形式。
本发明动物实验结果显示：（1）预先口服GGA ，2小时后注射吗啡，连续7天后，检测小鼠肝脏细胞内pro-caspase-9的表达情况。发现预先口服一定浓度的GGA，能够抑制吗啡导致的caspase-9的激活；（2）预先口服GGA，2小时后注射吗啡，连续7天后，检测小鼠肝脏细胞内caspase-3的表达情况，发现预先口服一定浓度的GGA，能够抑制吗啡导致的caspase-3的激活；（3）预先口服GGA，2小时后注射吗啡，连续7天后，检测小鼠肝脏细胞内丙二醛（MDA）的表达水平，发现预先口服一定浓度的GGA，能够抑制吗啡导致的丙二醛（MDA）的增加；上述实验结果表明在肝脏中GGA可以抑制吗啡所致的细胞凋亡和脂质过氧化损伤。因此，替普瑞酮可用于防治吗啡所致的肝脏损伤。
由于替普瑞酮在制备防治吗啡所致的肝脏损伤的药物中的作用是首次发现，因此，无论是GGA单独使用为活性成分制成的药剂，还是利用GGA防治吗啡所致的肝脏损伤的作用与其他活性成分配合使用制成的药剂，均在本专利的保护范围之内。
本发明的药物具有以下优点：（1）疗效显著；（2）安全性高；（3）价格低廉，可以减轻病人的经济负担。（4）老药新用，无需进行临床药物毒性的实验。
附图说明
图1是替普瑞酮在肝脏中抑制吗啡所致的caspase-9的激活的实验分析结果。
图2是替普瑞酮在肝脏中抑制吗啡所致的caspase-3的激活的实验分析结果。
图3是替普瑞酮在肝脏中抑制吗啡所致的丙二醛（MDA）的增加的实验分析结果。
图中“-”为不添加，“+”为添加。
具体实施方式
下面通过附图和实施例对本发明作进一步详细说明，但本发明保护范围不局限于所述内容。
本发明实施例中所用方法如无特别说明均为常规方法，本发明实施例中使用的细胞、试剂、材料取材、蛋白提取方法、蛋白免疫印迹法检测肝脏方法如下：
1、实验动物：SPF级C57BL/6小鼠，雄性，6-7周龄，体重22-25g，由重庆医科大学实验动物中心提供；小鼠单笼隔离饲养，饲喂专用饲料，自由饮食和饮水。
2、药品：替普瑞酮（日本卫材公司生产，分子量330.55），盐酸吗啡注射液（东北制药集团公司沈阳第一制药厂）, 丙二醛（MDA）ELISA试剂盒 （美国RD公司），抗caspase-9抗体和抗caspase-3抗体 （美国Santa Cruz公司）。
3、组织取材方法：小鼠猝死后，用生理盐水进行灌流，然后取出小鼠的肝脏组织，液氮冷冻后，-80℃保存。
4、蛋白提取：将肝脏组织在冰浴下匀浆，并加入700微升的细胞裂解液（150 mM NaCl，0.5% NP-40，10mM Tris-HCl，pH 7.2，0.1mM PMSF，2ug/ml aprotinin，200ug/ml NaN3），然后转移到离心管中，冰浴下放置裂解30min（中间振荡2～3次），4℃下15000 rpm离心15min，转上清至新离心管中，-80℃保存。
5、蛋白免疫印迹法
总蛋白加样量为20μg，与2×SDS凝胶加样缓冲液混合后，95℃热变性5 min，用15 %的SDS-PAGE胶电泳分离后，将蛋白条带电转移到PVDF膜上，用10 %脱脂牛奶4℃封闭过夜；取出PVDF膜，用含0.1 % Tween-20的TPBS冲洗后，加入500倍稀释的一抗室温孵育60 min；用含0.1% Tween-20的TPBS冲洗，加入10000倍稀释的二抗室温孵育60 min；用含0.1% Tween-20的TPBS冲洗，将PVDF膜浸入发光底物溶液中反应3 min后，用X射线胶片曝光。
实施例1：替普瑞酮在肝脏中抑制吗啡所致的caspase-9的激活
小鼠分成4组（每组6只）:对照组（saline）、吗啡组（Mor）、GGA和吗啡组（GGA+Mor）、GGA组。从第1天到7天，Saline组和Mor组预先灌胃给予生理盐水，GGA+Mor组和GGA组预先灌胃给予GGA(800 mg/kg)，2 h后，Saline组和GGA组腹腔注射生理盐水，Mor组和GGA+Mor组腹腔注射吗啡（每天注射的剂量为：10、20、40、60、80、100 and 100 mg/kg）。在最后一次吗啡注射2 h后，分离小鼠的肝脏组织，提取蛋白，用蛋白免疫印迹法检测肝脏细胞内pro-caspase-9的表达变化情况。图1结果显示，预先灌注GGA可以抑制吗啡所致的pro-caspase-9的减少，这说明替普瑞酮在肝脏中可抑制吗啡所致的caspase-9的激活，抵抗吗啡对线粒体的损伤。
实施例2：替普瑞酮在肝脏中抑制吗啡所致的caspase-3的激活
小鼠分成4组（每组6只）:对照组（saline）、吗啡组（Mor）、GGA和吗啡组（GGA+Mor）、GGA组。从第1天到7天， Saline组和Mor组预先灌胃给予生理盐水，GGA+Mor组和GGA组预先灌胃给予GGA(800 mg/kg)，2 h后，Saline组和GGA组腹腔注射生理盐水，Mor组和GGA+Mor组腹腔注射吗啡（每天注射的剂量为：10、20、40、60、80、100 and 100 mg/kg）。在最后一次吗啡注射2 h后，分离小鼠的肝脏组织，提取蛋白，用蛋白免疫印迹法检测肝脏细胞内caspase-3的表达变化情况。图2结果显示，预先灌注GGA可以抑制吗啡所致的active caspase-3的增加，这说明替普瑞酮在肝脏中可抑制吗啡所致的caspase-3的激活，抵抗吗啡所致的细胞凋亡。
实施例3：替普瑞酮在肝脏中抑制吗啡所致的丙二醛（MDA）的增加
小鼠分成4组（每组6只）:对照组（saline）、吗啡组（Mor）、GGA和吗啡组（GGA+Mor）、GGA组。从第1天到7天， Saline组和Mor组预先灌胃给予生理盐水，GGA+Mor组和GGA组预先灌胃给予GGA(800 mg/kg)，2 h后，Saline组和GGA组腹腔注射生理盐水，Mor组和GGA+Mor组腹腔注射吗啡（每天注射的剂量为：10、20、40、60、80、100 and 100 mg/kg）。在最后一次吗啡注射2 h后，分离小鼠的肝脏组织，在冰浴中用磷酸盐缓冲液制备成10 % 的匀浆，高速冷冻离心机离心10 min (4 ℃、4000 rpm条件下)，取上清液，使用丙二醛（MDA）ELISA试剂盒检测丙二醛（MDA）的含量。图3结果显示，预先灌注GGA可以抑制吗啡所致的丙二醛（MDA）的增加（与saline组小鼠对比，*p＜0.05；与Mor组小鼠对比，#p＜0.05）。这说明替普瑞酮在肝脏中可抑制吗啡所致的脂质过氧化，抵抗吗啡所致的氧化损伤。
Claims (1)
1.替普瑞酮在制备防治吗啡所致的肝脏损伤的药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210240755XA CN102764248A (zh) | 2012-07-12 | 2012-07-12 | 替普瑞酮防治吗啡所致的肝脏损伤的用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210240755XA CN102764248A (zh) | 2012-07-12 | 2012-07-12 | 替普瑞酮防治吗啡所致的肝脏损伤的用途 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102764248A true CN102764248A (zh) | 2012-11-07 |
Family
ID=47091979
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210240755XA Pending CN102764248A (zh) | 2012-07-12 | 2012-07-12 | 替普瑞酮防治吗啡所致的肝脏损伤的用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102764248A (zh) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101239069A (zh) * | 2007-02-05 | 2008-08-13 | 广州和竺生物科技有限公司 | 可提供活性甲基或参与甲基转移的化合物的应用 |
| CN102266312A (zh) * | 2011-06-23 | 2011-12-07 | 昆明理工大学 | 替普瑞酮在制备预防和/或治疗阿片类毒品成瘾药物中的应用 |
-
2012
- 2012-07-12 CN CN201210240755XA patent/CN102764248A/zh active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101239069A (zh) * | 2007-02-05 | 2008-08-13 | 广州和竺生物科技有限公司 | 可提供活性甲基或参与甲基转移的化合物的应用 |
| CN102266312A (zh) * | 2011-06-23 | 2011-12-07 | 昆明理工大学 | 替普瑞酮在制备预防和/或治疗阿片类毒品成瘾药物中的应用 |
Non-Patent Citations (1)
| Title |
|---|
| 沈爱玲: "替普瑞酮减轻脓毒症大鼠的脏器损伤", 《中国优秀硕士学位论文全文数据库医药卫生科技辑》, no. 2, 15 February 2012 (2012-02-15) * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2640115C2 (ru) | Фармацевтические композиции замещенных хиназолинонов | |
| Bermudez et al. | Current drug therapy and pharmaceutical challenges for Chagas disease | |
| Shi et al. | Icariin-mediated inhibition of NF-κB activity enhances the in vitro and in vivo antitumour effect of 5-fluorouracil in colorectal cancer | |
| Budde et al. | A phase I study of pulse high‐dose vorinostat (V) plus rituximab (R), ifosphamide, carboplatin, and etoposide (ICE) in patients with relapsed lymphoma | |
| KR20160022292A (ko) | 요산치 저하제 | |
| KR102166907B1 (ko) | 데커시놀 안젤레이트를 유효성분으로 포함하는 대장염 예방 또는 치료 조성물 | |
| Lu et al. | Autophagy in gastric mucosa: The dual role and potential therapeutic target | |
| US20160331714A1 (en) | The use of a benzoate containing composition in urea cycle disorders and neurodegenerative disorders | |
| CN102266312B (zh) | 替普瑞酮在制备预防和/或治疗阿片类毒品成瘾药物中的应用 | |
| Zhou et al. | Magnesium isoglycyrrhizinate ameliorates lipopolysaccharide-induced liver injury by upregulating autophagy and inhibiting inflammation via IL-22 expression | |
| CN109939119B (zh) | 栀子苷在制备治疗多发性硬化症药物中的应用 | |
| CN102764249B (zh) | 替普瑞酮防治吗啡所致的肾脏损伤的用途 | |
| CN102764248A (zh) | 替普瑞酮防治吗啡所致的肝脏损伤的用途 | |
| US20120058961A1 (en) | Pharmaceutical Composition for Treating Cancers | |
| KR20110117788A (ko) | 멜리틴을 포함하는 섬유아세포-유사-활막세포의 활성을 억제하는 조성물 | |
| Emmanuel et al. | COVID 19: Resveratrol as a Potential Supplement to Mitigate the Cardiotoxicity Associated with Chloroquine and Hydroxychloroquine Treatment | |
| EP3616754A1 (en) | Cancer treatment | |
| Lorenzo L et al. | Cancer pain managment with a venom of blue scorpion endemic in Cuba, called rhopalurus junceus “escozul” | |
| US9186339B2 (en) | Use of transcriptome modifying agents and chemotherapy or radiotherapy against cancer | |
| KR102235218B1 (ko) | 감마-테르피넨을 포함하는 자궁경부암 예방 또는 치료용 조성물 | |
| KR20230005187A (ko) | 염증성 및 섬유성 질환 및 장애를 치료하기 위한 방법 | |
| Chen et al. | Novel anti-leukemia activities of pipoxolan operate via the mitochondria-related pathway in human leukemia U937 cells and attenuate U937 cell growth in an animal model | |
| CN104922097A (zh) | 替普瑞酮在制备预防和/或治疗阿片类毒品复吸药物中的应用 | |
| Hou et al. | Ruthenium complex, TQ‑5, protects against LPS‑induced macrophage inflammation and acute liver injury in mice via downregulating NF‑κB pathways | |
| WO2018207792A1 (ja) | 血液脳関門保護剤 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20121107 |